Multicenter study of pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders.

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.

Burkitt lymphoma after solid-organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.

Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations.

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN).

BACKGROUND: Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies. METHODS: A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28-day cycle. PK and PD studies were performed. RESULTS: Twenty-one eligible patients' median (range) age was 14 years (6-20). Six subjects were treated at 3 mg/m2 dose level and 15 were treated in 4 mg/m2 dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose-limiting toxicity (DLT) was observed at either dose level. A three-fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses. CONCLUSIONS: Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2 orally administered once weekly.

Intracranial Myxoid Mesenchymal Tumor with Rare EWSR1-CREM Translocation.

Translocations between EWSR1 and members of the CREB family of transcription factors (CREB1, ATF1, and CREM) are rare genetic findings occurring in various sarcomas. Of these, the EWSR1-CREM translocation is the most rarely reported. We present the case of a 9-year-old boy who presented with a year of fatigue, weight loss, and abulia. A brain MRI revealed a frontal interhemispheric tumor arising from the falx. After resection, pathology demonstrated a myxoid mesenchymal tumor with an EWSR1-CREM translocation. A series of recent reports of similar tumors has generated ongoing debate in the literature over the classification of these tumors either as intracranial angiomatoid fibrous histiocytomas, which also harbor EWSR1-CREB family translocations, or as a novel diagnostic entity. The present case provides another example of the rare EWSR1-CREM fusion in an intracranial myxoid mesenchymal tumor that recurred in just 6 months despite gross total resection. The findings are discussed in the context of the existing literature and the ongoing effort to appropriately classify this type of tumor.

Paraspinal Desmoid Tumor in a Pediatric Patient with No Surgical History: A Case Report.

Desmoid tumors are locally aggressive, benign neoplasms originating in connective tissues. Although the exact pathophysiology remains unknown, antecedent trauma or surgery are believed to be important contributing factors. The occurrence of paraspinal desmoid tumor in pediatric patients is extremely uncommon. Here, we present an exceedingly rare case of a pediatric patient with no surgical or family history who developed a paraspinal desmoid tumor. A 9-year-old female patient presented with 4 months of progressive back pain, right lower extremity weakness, and numbness. Spinal imaging revealed a left epidural paraspinal mass compressing her thoracic spinal cord and extending into the left thoracic cavity. A multidisciplinary approach with neurosurgery and thoracic surgery enabled gross total resection of the lesion. The patient had complete resolution of her symptoms with no signs of residual tumor on postoperative imaging. Pathology revealed a desmoid tumor that avidly stained for beta-catenin. On her last follow-up, she developed a recurrence, to which she was started on sorafenib therapy. Desmoid tumors are rare connective tissue neoplasms that often occur after local tissue trauma, such as that caused by surgery. This report presents a rare case of a pediatric paraspinal desmoid tumor that occurred in a patient with no surgical or family history. Such tumors should undergo surgical resection for symptomatic relief and tissue diagnosis. Close clinical and radiographic surveillance are essential in these patients due to the high recurrence rates of desmoid tumor.

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921.

PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 µg h/mL, 2.52 µg h/mL, and 2.66 µg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.

Mixed phenotype acute leukemia in a child associated with a NUP98-NSD1 fusion and NRAS p.Gly61Arg mutation.

BACKGROUND: Mixed phenotype acute leukemia (MPAL) is a rare subset of acute leukemia in the pediatric population associated with genetic alterations seen in both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). CASE: We describe a patient with MPAL with a NUP98 (nucleoporin 98)-NSD1 gene fusion (nuclear receptor binding SET domain protein1) and NRAS (neuroblastoma RAS viral oncogene homolog mutation) p.Gly61Arg mutation who was treated with upfront AML-based chemotherapy, received hematopoietic stem cell transplant (HSCT), but unfortunately died from relapsed disease. CONCLUSION: This case highlights the challenges faced in choosing treatment options in MPAL patients with complex genomics, with predominant myeloid features.

A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study.

PURPOSE: Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. PATIENTS AND METHODS: Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m2) for 7-10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. RESULTS: Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9-20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2-17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m2 for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22-53.4). CONCLUSIONS: Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.

Liver Transplantation for Pediatric Liver Cancer.

Unresectable hepatocellular carcinoma (HCC) was first removed successfully with total hepatectomy and liver transplantation (LT) in a child over five decades ago. Since then, children with unresectable liver cancer have benefitted greatly from LT and a confluence of several equally important endeavors. Regional and trans-continental collaborations have accelerated the development and standardization of chemotherapy regimens, which provide disease control to enable LT, and also serve as a test of unresectability. In the process, tumor histology, imaging protocols, and tumor staging have also matured to better assess response and LT candidacy. Significant trends include a steady increase in the incidence of and use of LT for hepatoblastoma, and a significant improvement in survival after LT for HCC with each decade. Although LT is curative for most unresectable primary liver sarcomas, such as embryonal sarcoma, the malignant rhabdoid tumor appears relapse-prone despite chemotherapy and LT. Pediatric liver tumors remain rare, and diagnostic uncertainty in some settings can potentially delay treatment or lead to the selection of less effective chemotherapy. We review the current knowledge relevant to diagnosis, LT candidacy, and post-transplant outcomes for these tumors, emphasizing recent observations made from large registries or larger series.

Toxicity of Cancer Therapy in Adolescents and Young Adults (AYAs).

OBJECTIVES: To identify treatment-related toxicities that are either more frequent or more severe in the adolescent and young adult (AYA) oncology population. To explore differences in drug pharmacology and patient physiology that contribute to toxicities in the AYA population and to describe the impact of treatment-related toxicities on outcomes for AYA patients. DATA SOURCES: A PubMed search was undertaken using the key words Adolescent Young Adult Oncology, AYA, toxicity, bone marrow transplant, late effects, and chemotherapy. Additional toxicity information was also obtained from recent publications from cancer cooperative groups treating AYA patients. CONCLUSION: AYA patients often experience more severe toxicities than children when treated with identical chemotherapy regimens, which can interfere with successful administration of planned treatment, as well as have profound effects on quality of life. AYA patients with cancer face the dual challenge of disease biology associated with inferior response to treatment, thus necessitating treatment intensification, while at the same time suffering higher rates of specific toxicities such as vincristine-induced neuropathy, osteonecrosis, and treatment-related mortality caused by infection. IMPLICATIONS FOR NURSING PRACTICE: AYA patients are at a higher risk for toxicities from regimens that may be tolerated by younger patients. Staff should be aware of toxicities facing this population so that appropriate supportive care measures can be utilized. Future research on the pharmacology of drugs in adolescence, hormonal effects on drug-metabolizing enzymes, cumulative exposure to different drugs in combination, and risk and severity of specific toxicities will be critical to improving the treatment of AYA patients.

Medulloepithelioma with peculiar clinical presentation, stem cell phenotype and aberrant DNA-methylation profile.

We present a 21-year-old male with a neck mass diagnosed as medulloepithelioma. Despite aggressive chemo- and radio-therapy, the tumor metastasized and proved fatal after seventeen months. The tumor demonstrated robust immunohistochemical expression of multiple markers of embryonic/neural stem cells and embryogenesis from the paraffin embedded tissue. The tumor, expressing LIN28A but negative for the 19q13.42 amplicon, also lacked the characteristic methylation profile for medulloepithelioma and other tumors with similar morphology. The expression of embryonic markers may explain its unresponsiveness to therapy and poor prognosis. Therapies targeted at embryonic cell phenotypes may hold the key for successfully treating cancers with embryonal phenotypes or tumors harboring cells with embryonal phenotypes.